Conversion of Cefamandole Nafate to Cefamandole Sodium

By conventional laboratory evaluation procedures, the in vitro antibacterial activities of cefamandole and its O-formyl ester, cefamandole nafate, appear virtually identical. When the activities of these two compounds were exaniined for their ability to lyse log-phase cultures of susceptible bacteria, however, cefamandole was found to be about 10 times more active than cefamandole nafate. Cefamandole nafate was shown to be rapidly converted to cefamandole in bacteriological media, with a half-life of less than 1 h at a pH of 7.0 or above. At pH 6.0, in log-phase inhibition experiments, however, cefamandole nafate is more stable, allowing delineation of the activity between cefamandole and cefamandole nafate. The efficacy of cefamandole was identical to that of cefamandole nafate in treating experimental animal infections, indicating that rapid conversion of cefamandole nafate to cefamandole occurs in vivo.The antibacterial activity of cefamandole, 7-n-mandelamido-3f[(1-methyl-1H-tetrazol-5-yl)-thio]methyl}3-cephem-4-carboxylic acid, was first described by Wick and Preston (7)

Section: Resultsmentioning

confidence: 99%

Delineation of the Relative Antibacterial Activity of Cefamandole and Cefamandole Nafate

Turner

Preston

Wold

1977

“…Cefamandole nafate is the O-formyl ester of cefamandole and is the pharmaceutical preparation of choice because of its crystallinity and stability (4). Cefamandole nafate undergoes hydrolysis to free cefamandole and formate in vitro and in vivo (3,4,7). Although no difference is seen between cefamandole and cefamandole nafate in routine assay procedures, specially designed studies have demonstrated a potential difference in potency between cefamandole nafate and cefamandole, the latter showing a 5-to 10-fold-higher potency (5).…”

mentioning

confidence: 99%

Hydrolysis of cefamandole nafate in dialysis patients

Nielsen¹,

Wolen²,

Luft³

et al. 1979

The hydrolysis of cefamandole nafate was examined in vivo in five dialysis patients and five subjects with normal renal function. The plasma half-life of cefamandole was prolonged in the patients with renal failure compared with normal subjects (18.3 + 4.5 [standard deviation] versus 10.35 + 1.4 min, P < 0.01). The pharmacokinetics of cefamandole nafate best fit two-compartment, openmodel kinetics. We conclude that patients with severe renal failure are capable of hydrolyzing cefamandole nafate to cefamandole and formate at a rate sufficiently rapid so as not to allow an accumulation of cefamandole nafate. The difference in half-life may be related to urinary excretion of cefamandole nafate in normal individuals.Cefamandole is a new broad-spectrum cephalosporin antibiotic (6). Cefamandole nafate is the O-formyl ester of cefamandole and is the pharmaceutical preparation of choice because of its crystallinity and stability (4). Cefamandole nafate undergoes hydrolysis to free cefamandole and formate in vitro and in vivo (3, 4, 7). Although no difference is seen between cefamandole and cefamandole nafate in routine assay procedures, specially designed studies have demonstrated a potential difference in potency between cefamandole nafate and cefamandole, the latter showing a 5-to 10-fold-higher potency (5). Knowledge of the hydrolysis of cefamandole nafate in vivo may be of clinical importance (5), particularly if cefamandole nafate accumulates due to slow hydrolysis in patients with renal failure. The hydrolysis of cefamandole nafate in patients with diminished renal function has not been described. The present report describes the hydrolysis of the O-formyl ester in five patients with severe chronic renal failure as compared with five subjects with normal renal function.Ten subjects, five with normal renal function and five chronic hemodialysis patients, were studied. The normal subjects ranged in age from 22 to 37 years (mean, 29 years), compared to 43 to 70 years (mean, 61 years) for the dialysis patients. The mean surface area (Dubois method) was 1.84 ± 0.11 (standard deviation) m2 in normal subjects and 1.66 ± 0.24 (standard deviation) m2 in the renal failure group (P > 0.05). The dialysis patients, who were all studied during the intradialytic period, were all oliguric and had endogenous creatinine clearance rates of <2 ml/min. Approval for these studies was obtained from the Indiana University Committee on the Use of Human Subjects in Research.Written informed consent was obtained from all participants.The cefamandole nafate formulation (Eli Lilly & Co.) contained 1.11 g of cefamandole and 68 mg of sodium carbonate in each vial. Vials were diluted with 5% glucose in water and allowed to stand for precisely 15 min before infusion. Upon dilution the initial alkaline pH (ca. 9.0) rapidly falls, with some hydrolysis of the ester to cefamandole and formate (4). Slowing of the hydrolysis occurs as the pH reaches 6 in approximately 5 min, and a very slow hydrolysis takes place thereafter. The 15-min period was chose...

“…Cefamandole nafate (I), the formyl ester of cefamandole (II), was chosen as the pharmaceutical form of this cephalosporin antibiotic because of its crystallinity and resulting dry state stability (3) (Fig. 1).…”

mentioning

confidence: 99%

“…1). It is readily converted to cefamandole in vitro in a pH-dependent reaction (3). The hydrolysis of the formyl moiety begins upon solution in water and is facilitated by the presence of Na2C03.…”

mentioning

confidence: 99%

Metabolic Fate of [ ¹⁴ C]Cefamandole, a Parenteral Cephalosporin Antibiotic, in Rats and Dogs

Sullivan

Due

Kau

et al. 1977

The biotransformation of the parenterally effective cephalosporin antibiotic cefamandole nafate (I) has been studied in rats and dogs. After rapid in vivo hydrolysis of the nafate pharmaceutical form to cefamandole (II), the antibiotic was found to be very resistant to metabolic degradation in both species. In dogs, cefamandole escaped metabolism and was eliminated as unaltered antibiotic almost exclusively by renal excretion. In rats, cefamandole was somewhat labile to metabolism; however, a major portion of the administered antibiotic was eliminated unchanged principally by renal excretion.